The present invention relates to aminoethylphenoxyacetic acid derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments.
Urolithiasis is a disease generating calculi by a series of events such as nucleation of the urinary component, crystallization, aggregation, concretion and enlargement in the lumen of the entire urinary tract from the kidney to the urethra. Urinary flow is often obstructed by calculi, which results in the rise of intra-ureteral pressure, leading to pain. At present, an analgesic and an antispastic are prescribed for the pain. However, the use of the analgesic is only a temporary symptomatic therapy for the pain, and is not expected to treat urolitiasis fundamentally at all. The effectiveness of the antispastic such as an anti-cholinergic is also not satisfactory. Therefore, useful drugs for the causual treatment of urolithiasis, for example, the drugs which relieve pain and promote the removal of calculi by widening the ureter with their strong relaxing effects are desired (The Journal of Urology, Vol.152, pp.1095-1098 (1994)).
It was recently confirmed that both xcex22- and xcex23-adrenoceptors are present in human ureter as xcex2-adrenoceptor subtypes. It is reported that a drug having stimulating effects on both xcex22- and xcex23-adrenoceptors is extremely useful as an agent for relieving pain and promoting the removal of calculi in urolithiasis because a compound having stimulating effects on both xcex22- and xcex23-adrenoceptors shows potent relaxing effects on ureter (International application publication No. WO97/19700).
The present inventors have studied earnestly to find compounds being useful as agents for relieving pain and promoting the removal of calculi in urolithiasis. As a result, it was found that certain aminoethylphenoxyacetic acid derivatives have potent stimulating effects on both xcex22- and xcex23-adrenoceptors and show excellent ureteral relaxation effects, thereby forming the basis of the present invention.
The present invention relates to aminoethylphenoxyacetic acid derivatives represented by the general formula: 
(wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom or a halogen atom; the carbon atom marked with (R) represents a carbon atom in (R) configuration; and the carbon atom marked with (S) represents a carbon atom in (S) configuration) and pharmaceutically acceptable salts thereof.
The present invention relates to pharmaceutical compositions comprising an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to agents for relieving pain and promoting the removal of calculi which comprises as the active ingredient an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to methods for relieving pain and promoting the removal of calculi in urolithiasis which comprises administering a therapeutically effective amount of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to uses of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of urolithiasis.
The present invention relates to uses of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as agents for relieving pain and promoting the removal of calculi in urolithiasis.
The present invention relates to processes for the manufacture of a pharmaceutical composition for the treatment of urolithiasis, characterized in the use, as an essential constituent of said pharmaceutical composition, of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
In the present invention, the term xe2x80x9clower alkyl groupxe2x80x9d means an alkyl group having from 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and a hexyl group; the term xe2x80x9caralkyl groupxe2x80x9d means the above lower alkyl group substituted by an aryl group such as a phenyl group and a naphthyl group; and the term xe2x80x9chalogen atomxe2x80x9d means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The compounds represented by the above general formula (I) of the present invention can be prepared according to the following procedures. For example, the compounds of the present invention can be prepared by subjecting a phenylpropanolamine derivative represented by the formula: 
(wherein the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) to alkylation using an alkylating agent represented by the general formula: 
(wherein R1a represents a lower alkyl group or an aralkyl group; X1 represents a chlorine atom or a bromine atom; and R2 has the same meaning as defined above), and hydrolyzing the ester group of the resulting compound in the usual way as occasion demands.
Of the compounds represented by the above general formula (I) of the present invention, compounds represented by the general formula: 
(wherein R1a, R2, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) can be also prepared by esterification of the corresponding aminoethylphenoxyacetic acid derivative (compounds represented by the general formula (Ib) described below).
The phenylpropanolamine derivative represented by the above formula (II) used as a starting material in the above production process can be prepared by optical resolution of a commercially available enantiomeric mixture in the usual way or a method described in a literature (J. Med. Chem., Vol. 20, No. 7, pp. 978-981(1977)).
The alkylating agents represented by the above general formula (III) used as starting materials in the above production process can be prepared by allowing an anisole derivative represented by the general formula: 
(wherein R2 has the same meaning as defined above) to react with a compound represented by the general formula: 
(wherein X2 represents a chlorine atom or a bromine atom; and X1 has the same meaning as defined above) in the presence of a Lewis acid such as aluminum chloride, removing the methyl group as occasion demands, reducing the carbonyl group using a reducing agent such as triethylsilane to give a phenol derivative represented by the general formula: 
(wherein R2 and X1 have the same meanings as defined above), and allowing the resulting compound to react with an alkyl halogenoacetate in the presence of a base such as potassium carbonate.
The aminoethylphenoxyacetic acid derivatives represented by the above general formula (I) of the present invention obtained by the above production processes can be readily isolated and purified by conventional separation means such as fractional recrystallization, purification using column chromatography and solvent extraction.
The aminoethylphenoxyacetic acid derivatives represented by the above general formula (I) of the present invention can be converted into their pharmaceutically acceptable salts in the usual way. Examples of the such salts include acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, acid addition salts formed with organic acids such as formic acid, acetic acid, propionic acid, citric acid, tartaric acid, fumalic acid, butyric acid, oxalic acid, succinic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, inorganic base salts such as a sodium salt, a potassium salt, a calcium salt and an ammonium salt, and salts formed with organic bases such as triethylamine, piperidine, morpholine, pyridine and lysine.
In addition, the compounds represented by the above general formula (I) of the present invention also include their solvates with pharmaceutically acceptable solvents such as water and ethanol.
xcex22-Adrenoceptor stimulating effects of the compounds represented by the above general formula (I) of the present invention can be measured by using pregnant rat uterus. For example, EC50 value (the concentration inhibiting 50% of the spontaneous contraction) of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-acetic acid was 3.1xc3x9710xe2x88x928M.
xcex23-Adrenoceptor stimulating effects of the compounds represented by the above general formula (I) of the present invention can be measured by using ferret ureter. For example, EC50 value (the concentration inhibiting 50% of the spontaneous contraction) of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-acetic acid was 1.4xc3x9710xe2x88x928M.
Thus, the compounds represented by the above general formula (I) of the present invention have potent stimulating effects on both xcex22- and xcex23-adrenoceptors and are useful as agents for relieving pain and promoting the removal of calculi such as spontaneous passage of calculi and the removal of the calculi after extracorporeal shock wave lithotripsy in urolithiasis.
In the present invention, compounds with less xcex21-adrenoceptor stimulating effects in comparison with the above xcex22- and xcex23-adrenoceptor stimulating effects are preferable so as to reduce burdens on the heart and not to induce side effects such as tachycardia. Some compounds of the present invention are xcex22- and xcex23-adrenoceptor stimulants with less xcex21-adrenoceptor stimulating effects. As examples of such compounds, compounds represented by the general formula: 
(wherein R2, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) and pharmaceutical acceptable salts thereof can be illustrated.
As more preferable compounds in the present invention, 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenoxy]acetic acid, 2-[3-fluoro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid and pharmaceutically acceptable salts thereof can be illustrated.
For example, in the experiment for measuring xcex21-adrenoceptor stimulating effects using rat atrium, 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid showed ECxcex9420 value (the concentration to increase the heart rate by 20 beats per minute) at a concentration of 1.3xc3x9710xe2x88x926 M.
Furthermore, the compounds represented by the above general formula (I) of the present invention are highly safe. For example, in acute toxicity test using rats, any dead rats were not observed by a single administration of 1,000 mg/kg of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid.
In consequence, the compounds represented by the above general formula (I) of the present invention and pharmaceutically acceptable salts thereof have potent and extremely useful stimulating effects on both xcex22- and xcex23-adrenoceptors.
When the aminoethylphenoxyacetic acid derivatives represented by the above general formula (I) of the present invention and pharmaceutically acceptable salts thereof are employed in the practical treatment, they are administered orally or parenterally in the form of appropriate pharmaceutical compositions such as tablets, powders, fine granules, granules, capsules, injections and the like. These pharmaceutical compositions can be formulated in accordance with conventional methods using conventional pharmaceutical carriers, excipients and other additives.
The dosage is appropriately decided depending on the sex, age, body weight, degree of symptoms and the like of each patient to be treated, which is approximately within the range of from 1 to 1,000 mg per day per adult human in the case of oral administration and approximately within the range of from 0.01 to 100 mg per day per adult human in the case of parenteral administration, and the daily dose can be divided into one to several doses per day.